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The Journal of Pharmacology and... Sep 2019Induction of lysosomal exocytosis alleviates lysosomal storage of undigested metabolites in cell models of lysosomal disorders (LDs). However, whether this strategy...
Induction of lysosomal exocytosis alleviates lysosomal storage of undigested metabolites in cell models of lysosomal disorders (LDs). However, whether this strategy affects other vesicular compartments, e.g., those involved in endocytosis, is unknown. This is important both to predict side effects and to use this strategy in combination with therapies that require endocytosis for intracellular delivery, such as lysosomal enzyme replacement therapy (ERT). We investigated this using -tocopherol as a model previously shown to induce lysosomal exocytosis and cell models of type A Niemann-Pick disease, a LD characterized by acid sphingomyelinase (ASM) deficiency and sphingomyelin storage. -Tocopherol and derivative CF3-T reduced net accumulation of fluid phase, ligands, and polymer particles via phagocytic, caveolae-, clathrin-, and cell adhesion molecule (CAM)-mediated pathways, yet the latter route was less affected due to receptor overexpression. In agreement, -tocopherol lowered uptake of recombinant ASM by deficient cells (known to occur via the clathrin pathway) and via targeting intercellular adhesion molecule-1 (associated to the CAM pathway). However, the net enzyme activity delivered and lysosomal storage attenuation were greater via the latter route. Data suggest stimulation of exocytosis by tocopherols is not specific of lysosomes and affects endocytic cargo. However, this effect was transient and became unnoticeable several hours after tocopherol removal. Therefore, induction of exocytosis in combination with therapies requiring endocytic uptake, such as ERT, may represent a new type of drug interaction, yet this strategy could be valuable if properly timed for minimal interference.
Topics: Animals; Cell Adhesion Molecules; Cells, Cultured; Combined Modality Therapy; Drug Interactions; Endocytosis; Enzyme Replacement Therapy; Exocytosis; Humans; Nanoparticles; Niemann-Pick Disease, Type A; Recombinant Proteins; Sphingomyelin Phosphodiesterase; Tocopherols
PubMed: 31101681
DOI: 10.1124/jpet.119.257345 -
Foods (Basel, Switzerland) Jun 2022This study was the first time the effects of pretreatment technology (microwave roasting, MR; oven roasting, OR; steaming roasting, SR) and processing technology (screw...
This study was the first time the effects of pretreatment technology (microwave roasting, MR; oven roasting, OR; steaming roasting, SR) and processing technology (screw pressing, SP; aqueous enzymatic extraction, AEE; subcritical butane extraction, SBE) on the quality (physicochemical properties, phytochemical content, and antioxidant ability) of walnut oil were systematically compared. The results showed that the roasting pretreatment would reduce the lipid yield of walnut oil and SBE (59.53−61.19%) was the processing method with the highest yield. SR-AEE oil provided higher acid value (2.49 mg/g) and peroxide value (4.16 mmol/kg), while MR-SP oil had the highest content of polyunsaturated fatty acid (73.69%), total tocopherol (419.85 mg/kg) and total phenolic compounds (TPC, 13.12 mg/kg). The DPPH-polar and ABTS free radicals’ scavenging abilities were accorded with SBE > AEE > SP. SBE is the recommended process for improving the extraction yield and antioxidant ability of walnut oil. Hierarchical cluster analysis showed that processing technology had a greater impact on walnut oil than pretreatment technology. In addition, multiple linear regression revealed C18:0, δ-tocopherol and TPC had positive effects on the antioxidant ability of walnut oil, while C18:1n-9, C18:3n-3 and γ-tocopherol were negatively correlated with antioxidant activity. Thus, this a promising implication for walnut oil production.
PubMed: 35741896
DOI: 10.3390/foods11121698 -
Turkish Journal of Urology Jul 2019Obstructive bladder dysfunction (OBD) caused by benign prostatic hyperplasia is a common medical problem in ageing men. As the prostate enlarges and compresses the...
OBJECTIVE
Obstructive bladder dysfunction (OBD) caused by benign prostatic hyperplasia is a common medical problem in ageing men. As the prostate enlarges and compresses the urethra, the bladder wall thickness and the bladder is termed "compensated" because its function is still relatively normal. Subsequently, bladder function begins to fail and this change is termed "decompensation." The extent of decompensation progresses from mild through severe. Bladder decompensation is mediated by cyclical ischemia followed by reperfusion (I/R) resulting in an increased generation of free radicals and oxidative stress. Previous studies demonstrated that both vitamin E (tocopherol) and alpha-lipoic acid (LA) showed significant antioxidant activity in experimental urinary bladder oxidative stress models. We hypothesized that co-drugs derived from these antioxidants would result in enhanced antioxidant activity relative to either individual compound for the treatment of oxidative stress in the lower urinary tract.
MATERIAL AND METHODS
Two ester co-drugs of TOC and LA, tocopherol ester (α-TOCE) and δ-TOCE were synthesized. Six adult male New Zealand White (NZW) rabbits were divided into two groups of three rabbits each. Eight full thickness strips from each rabbit bladder were taken for in vitro I/R experiments. The strips from the first set were control rabbits (24 strips). Six strips were not incubated, while the remaining strips were incubated in α-TOCE dissolved in 1% (n=6) or 2.5% ethanol (n=6) solutions. These strips were not subjected to in vitro I/R. The strips from the second set were processed as follows: 6 strips were not incubated, while the remaining strips were incubated in α-TOCE dissolved in 1% (n=6) or in δ-TOCE dissolved in 2.5% ethanol. These strips were subjected to 1 hour in vitro ischemia followed by two hours reperfusion.
RESULTS
Preliminary studies demonstrated that neither antioxidant had any effect on the contractile responses to 1% or 2.5% ethanol. Neither antioxidant had any effect on the control contractile responses. Both antioxidants protected the tissue from the initial effects of ischemia. Both antioxidants had significant protective effects on the contractile responses to all forms of stimulation after the reperfusion period.
CONCLUSION
Incubation with both antioxidants had similar protective effects on responses both to ischemia and to reperfusion.
PubMed: 30817293
DOI: 10.5152/tud.2018.48154 -
Plants (Basel, Switzerland) Mar 2023The seeds of 111 sp. different fruit use (dessert and cider apples) cultivars/genotypes developed in 18 countries were analysed to evaluate composition of tocopherol...
The seeds of 111 sp. different fruit use (dessert and cider apples) cultivars/genotypes developed in 18 countries were analysed to evaluate composition of tocopherol homologues and identify crop-specific profile, including diploid, triploid, and tetraploid apple cultivars with and without scab-resistance to ensure high genetic diversity. The percentage of individual tocopherols was as follows: alpha-tocopherol (alpha-T) (38.36%), beta-tocopherol (beta-T) (40.74%), gamma-tocopherol (gamma-T) (10.93%), and delta-tocopherol (delta-T) (9.97%), represented by average measurements of 17.48, 18.56, 4.98, and 4.54 mg/100 g dry weight, respectively. The values of the variation coefficient showed high variability for delta (0.695) and gamma (0.662) homologue content, whereas measurements of alpha-T and beta-T were less variable (coefficient of variation 0.203 and 0.256, respectively). The unweighted pair group method with arithmetic mean (UPGMA) revealed three main cultivar groups characterised by almost equal content of all four tocopherol homologues (Group I), high concentrations of alpha-T and beta-T, but very low content of gamma-T and delta-T (Group II), and relatively high average content of alpha-T and beta-T, but higher gamma-T and delta-T content (Group III). Specific tocopherol homologues showed association with certain valuable traits, such as harvesting time (total content of tocopherols) and resistance to apple scab (alpha-T and total content of tocopherols). This study represents the first large-scale tocopherol homologue (alpha, beta, gamma, and delta) screening in apple seeds. The dominant tocopherol homologues in cultivated apple cultivars are alpha-T and beta-T, with the prevalence of alpha-T or beta-T depending on genotype. It is a unique finding due to the rare occurrence of beta-T in the plant world and is considered a unique feature of the species.
PubMed: 36904029
DOI: 10.3390/plants12051169 -
Evidence-based Complementary and... 2022Uremic pruritus is a frequent and prominent symptom in patients with advanced or end-stage renal disease. Lack of an effective treatment for kidney disease-associated... (Review)
Review
Uremic pruritus is a frequent and prominent symptom in patients with advanced or end-stage renal disease. Lack of an effective treatment for kidney disease-associated pruritus often leads to many problems for these patients and makes it difficult to choose an appropriate treatment. The purpose of this evidence-based hypothesis is to share the scientific reasons and related mechanisms in order to claim that lettuce could be useful in the treatment of uremic pruritus. This hypothesis is based on studies related to lettuce and its anti-inflammatory, antioxidant, antidiabetic, sedative, hypnotic, nephroprotective, potassium balancing, and blood purification properties. As a result, we suggest that lettuce could be a good choice for improving and reducing uremic pruritus due to its certain characteristics. Although proof of this hypothesis requires further clinical trial studies, this hypothesis can nevertheless lead to formulating an appropriate therapy for uremic-induced pruritus. By conducting a molecular docking study, we investigated the interactions between nineteen natural bioactive components of lettuce () and human kappa opioid receptors. The docking studies revealed that most of the ligands showed better antipruritic efficacy than gabapentin. Gamma-tocopherol, delta-tocopherol, and campesterol demonstrated the highest binding affinities toward the target protein.
PubMed: 35392648
DOI: 10.1155/2022/4231854 -
Molecules (Basel, Switzerland) Oct 2020This investigation included the chemical analysis of () seed oil and its antifungal properties against 10 fungal species. Seed oils of six populations were analyzed...
This investigation included the chemical analysis of () seed oil and its antifungal properties against 10 fungal species. Seed oils of six populations were analyzed using high performance liquid chromatography (HPLC) and gas chromatograph/mass spectrometry (GC-MS). The HPLC analysis indicated that . seed oil exhibited a very high level of tocopherol contents, with values in the range of 2385.66-2722.68 mg/100 g. The most abundant tocopherol isomer was δ-tocopherol (90.39%), followed by γ-tocopherol (8.08%) and α-tocopherol (1.14%). We discovered for the first time the presence of tocotrenols in seed oils of the six populations studied. The GC-MS analyses revealed that linoleic acid was the main fatty acid (65.17%), followed by oleic acid (23.12%), palmitic acid (5.36%) and stearic acid (3.08%). We also studied the antifungal activity of seed oil of the Medenine (MD) population on ten fungal pathogens. The antifungal effects differed among pathogens and depended on oil concentrations. Seed oil of the MD population caused a significant decrease in mycelial growth of all fungi tested, with values ranging 31.50-82.11%, except for sp., which showed no inhibition. The antifungal activity against the 10 selected fungi can be explained by the richness in tocols of the extracted oil and make a promising crop for biological control. Furthermore, the importance of fatty acids and the wide geographic spread in Tunisia of this species make this crop a potential source of renewable energy.
Topics: Antifungal Agents; Fungi; Gas Chromatography-Mass Spectrometry; Linoleic Acid; Oleic Acid; Palmitic Acid; Peganum; Plant Oils; Seeds; Tocopherols
PubMed: 33036316
DOI: 10.3390/molecules25194569 -
Plant Physiology Nov 2019Tocopherols are lipid-soluble antioxidants synthesized in plastids of plants and other photosynthetic organisms. The four known tocopherols, α-, β-, γ-, and...
Tocopherols are lipid-soluble antioxidants synthesized in plastids of plants and other photosynthetic organisms. The four known tocopherols, α-, β-, γ-, and δ-tocopherol, differ in number and position of methyl groups on their chromanol head group. In unstressed Arabidopsis () leaves, α-tocopherol constitutes the main tocopherol form, whereas seeds predominantly contain γ-tocopherol. Here, we show that inoculation of Arabidopsis leaves with the bacterial pathogen induces the expression of genes involved in early steps of tocopherol biosynthesis and triggers strong accumulation of γ-tocopherol, moderate production of δ-tocopherol, and generation of the benzoquinol precursors of tocopherols. The pathogen-inducible biosynthesis of tocopherols is promoted by the immune regulators ENHANCED DISEASE SUSCEPTIBILITY1 and PHYTOALEXIN-DEFICIENT4. In addition, tocopherols accumulate in response to bacterial flagellin and reactive oxygen species. By quantifying tocopherol forms in inoculated wild-type plants and biosynthetic pathway mutants, we provide biochemical insights into the pathogen-inducible tocopherol pathway. Notably, () mutant plants, which are compromised in both tocopherol and benzoquinol precursor accumulation, exhibit increased susceptibility toward compatible and possess heightened levels of markers of lipid peroxidation after bacterial infection. The deficiency of triunsaturated fatty acids in () quadruple mutants prevents increased lipid peroxidation in the background and restores pathogen resistance to wild-type levels. Therefore, the tocopherol biosynthetic pathway positively influences salicylic acid accumulation and guarantees effective basal resistance of Arabidopsis against compatible , possibly by protecting leaves from the pathogen-induced oxidation of trienoic fatty acid-containing lipids.
Topics: Arabidopsis; Arabidopsis Proteins; Carboxylic Ester Hydrolases; DNA-Binding Proteins; Gene Expression Regulation, Plant; Plant Immunity; Plant Leaves; Pseudomonas syringae; Tocopherols
PubMed: 31515446
DOI: 10.1104/pp.19.00618 -
Free Radical Biology & Medicine Feb 2022Natural forms of vitamin E comprise four tocopherols and four tocotrienols. During the last twenty years, there have been breakthroughs in our understanding of vitamin E...
Natural forms of vitamin E comprise four tocopherols and four tocotrienols. During the last twenty years, there have been breakthroughs in our understanding of vitamin E metabolism and biological activities of vitamin E metabolites. Research has established that tocopherols and tocotrienols are metabolized via ω-hydroxylase (CYP4F2)-initiated side chain oxidation to form 13'-hydroxychromanol and 13'-carobyxychromanol (13'-COOH). 13'-COOHs are further metabolized via β-oxidation and sulfation to intermediate carboxychromanols, terminal metabolite carboxyethyl-hydroxychroman (CEHC), and sulfated analogs. Animal and human studies show that γ-, δ-tocopherol and tocotrienols are more extensively metabolized than α-tocopherol (αT), as indicated by higher formation of CEHCs and 13'-COOHs from non-αT forms than those from αT. 13'-COOHs are shown to be inhibitors of cyclooxygenase-1/-2 and 5-lipoxygenase and much stronger than CEHCs for these activities. 13'-COOHs inhibit cancer cell growth, modulate cellular lipids and activate peroxisome proliferator-activated receptor-γ and pregnane X receptor. Consistent with mechanistic findings, αT-13'-COOH or δTE-13'-COOH, respective metabolites of αT or δ-tocotrienol, show anti-inflammatory and cancer-preventive effects, modulates the gut microbiota and prevents β-amyloid formation in mice. Therefore, 13'-COOHs are a new class of bioactive compounds with anti-inflammatory and anti-cancer activities and potentially capable of modulating lipid and drug metabolism. Based on the existing evidence, this author proposes that metabolites may contribute to disease-preventing effects of γ-, δ-tocopherol and tocotrienols. The role of metabolites in αT's actions may be somewhat limited considering controlled metabolism of αT because of its association with tocopherol-transport protein and less catabolism by CYP4F2 than other vitamin E forms.
Topics: Animals; Mice; Neoplasms; Tocopherols; Tocotrienols; Vitamin E; alpha-Tocopherol
PubMed: 34785321
DOI: 10.1016/j.freeradbiomed.2021.11.012 -
Frontiers in Cellular Neuroscience 2022The amyloid precursor protein (APP) processing pathway was altered in Alzheimer's disease (AD) and contributed to abnormal amyloid-beta (Aβ) production, which forms...
The amyloid precursor protein (APP) processing pathway was altered in Alzheimer's disease (AD) and contributed to abnormal amyloid-beta (Aβ) production, which forms insoluble interneuron protein aggregates known as amyloid plaques in the brain. Targeting the APP processing pathway is still fundamental for AD modifying therapy. Extensive research has evaluated the protective effects of vitamin E as an antioxidant and as a signaling molecule. The present study aimed to investigate the modulatory effects of different tocopherol isomers on the expression of genes involved in regulating the APP processing pathway . The screening for the effective tocopherol isomers in reducing APP expression and Aβ-42 was carried out in SH-SY5Y stably overexpressed APP Swedish. Subsequently, quantitative one-step real-time PCR was performed to determine the modulatory effects of selected tocopherol isomers on the expression of genes in SH-SY5Y stably overexpressed three different types of APP (wild-type, APP Swedish, and APP Swedish/Indiana). Our results showed that all tocopherol isomers, especially at higher concentrations (80-100 μM), significantly increased ( < 0.05) the cell viability in all cells group, but only α-tocopherol (ATF) and γ-tocopherol (GTF) significantly decreased ( < 0.05) the APP mRNA level without statistically significant APP protein level, accompanied with a reduced significance ( < 0.05) on the level of Aβ-42 in SH-SY5Y APP Swedish. On the other hand, β- and δ-tocopherol (BTF and DTF) showed no effects on the level of APP expression and Aβ-42. Subsequent results demonstrated that ATF and GTF significantly decreased ( < 0.05) the expression of gene beta-site APP cleaving enzyme (), , and Nicastrin (), but significantly increased ( < 0.05) the expression of Sirtuin 1 () in SH-SY5Y stably expressed the mutant APP form. These findings suggested that ATF and GTF could modulate altered pathways and may help ameliorate the burden of amyloid load in AD.
PubMed: 35614968
DOI: 10.3389/fncel.2022.846459 -
Molecules (Basel, Switzerland) Jul 2021A fast HPLC method with fluorescence detector (FD) was developed for the determination of three tocopherols (TOCs) in milk samples from cattle breed. The...
A fast HPLC method with fluorescence detector (FD) was developed for the determination of three tocopherols (TOCs) in milk samples from cattle breed. The ultrasound-assisted procedure was optimized for the extraction of TOCs prior to HPLC/FD analysis, reducing sample preparation time and allowing a fast quantification of α-tocopherol, δ-tocopherol and γ tocopherol. The optimized ultrasonic extraction combines an efficient and simple saponification at room temperature and a rapid HPLC quantification of TOCs in milk. The precision of the full analytical procedure was satisfactory and the recoveries at three spiked levels were between 95.3% and 87.8%. The linear correlations were evaluated (R > 0.99) and the relative standard deviation (RSD) values for intra-day and inter-day tests at three spiked levels were below 1% for the retention time and below 5.20% for the area at low level spiking. The proposed procedure, reducing the experimental complexity, allowed accurate extraction and detection of three TOCs in milk samples from cattle breed.
Topics: Animals; Cattle; Chromatography, High Pressure Liquid; Limit of Detection; Liquid-Liquid Extraction; Milk; Observer Variation; Reproducibility of Results; Saponins; Sonication; Time Factors; Tocopherols; alpha-Tocopherol; gamma-Tocopherol
PubMed: 34361798
DOI: 10.3390/molecules26154645